Lemborexant and related sleep medicines present potential for treating tau-related issues, together with Alzheimer’s illness.
New analysis from Washington College College of Medication in St. Louis reveals {that a} generally used sleep remedy can restore regular sleep patterns and defend mice from the mind injury linked to neurodegenerative situations similar to Alzheimer’s illness. The drug, lemborexant, blocks the buildup of an irregular type of the tau protein within the mind, thereby decreasing the irritation and mobile damage that tau sometimes causes in Alzheimer’s.
The findings point out that lemborexant, together with different medicines that act in the same approach, might maintain promise for treating or stopping tau-related injury in a number of neurodegenerative issues, together with Alzheimer’s illness, progressive supranuclear palsy, corticobasal syndrome, and sure types of frontotemporal dementia.
The examine was not too long ago printed within the journal Nature Neuroscience.
Linking sleep loss and tau buildup
“We’ve got identified for a very long time that sleep loss is a threat issue for Alzheimer’s illness,” mentioned senior creator David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology at WashU Medication. “On this new examine, we’ve proven that lemborexant improves sleep and reduces irregular tau, which seems to be a most important driver of the neurological injury that we see in Alzheimer’s and several other associated issues. We’re hopeful this discovering will result in additional research of this sleep remedy and the event of latest therapeutics that could be simpler than present choices both alone or together with different obtainable therapies.
“The antibodies to amyloid that we now use to deal with sufferers with early, delicate Alzheimer’s dementia are useful, however they don’t gradual the illness down as a lot as we wish,” he added. “We’d like methods to scale back the irregular tau buildup and its accompanying irritation, and such a sleep help is price taking a look at additional. We’re considering whether or not going after each amyloid and tau with a mixture of therapies might be simpler at slowing or stopping the development of this illness.”
Testing lemborexant in mouse fashions
Holtzman and his colleagues had been among the many first to show that poor sleep is a threat issue for Alzheimer’s illness, carefully linked to the buildup of proteins similar to amyloid and tau. In earlier research utilizing mice genetically predisposed to develop these protein deposits, they confirmed that sleep loss accelerates this buildup. Their latest analysis revealed that bettering sleep in these mice with lemborexant diminished tau tangles and lowered the extent of nerve cell demise sometimes related to Alzheimer’s illness.
Tau protein accumulates within the mind in a number of neurological issues, together with Alzheimer’s, the place it triggers irritation and the degeneration of neurons. Holtzman’s group, with Samira Parhizkar, PhD, as first creator, investigated lemborexant partly as a result of it targets mind areas particularly susceptible to irregular tau buildup. Importantly, it doesn’t intervene with motor coordination, a problem typically raised when contemplating sleep medicines for folks with dementia.
Mechanism of motion and comparisons
Lemborexant belongs to a category of three FDA-approved sleep medicines that act as orexin receptor antagonists. Orexins are small proteins that regulate sleep by binding to receptors on cell surfaces. By blocking each orexin receptor sorts (1 and a pair of), lemborexant disrupts orexin exercise, influencing the sleep-wake cycle and associated processes similar to urge for food regulation.
The pharmaceutical firm Eisai supplied lemborexant for these research as a part of a analysis collaboration with WashU Medication centered on creating progressive therapies for Alzheimer’s illness, Parkinson’s illness, and different neurodegenerative ailments.
In mice genetically liable to dangerous tau buildup, lemborexant diminished mind injury in contrast with management mice. For instance, these receiving lemborexant confirmed 30% to 40% bigger quantity within the hippocampus — part of the mind necessary for forming recollections — in contrast with management mice and people receiving a distinct sleep drug, zolpidem, which belongs to a distinct class of medicine. Zolpidem elevated sleep however had not one of the protecting results towards tau accumulation within the mind that had been seen with lemborexant, suggesting that the kind of sleep help — orexin receptor antagonist — is essential in producing the neuroprotective results. The researchers additionally discovered that the useful results had been solely seen in male mice, which they’re nonetheless working to grasp.
Regular tau is necessary in sustaining the construction and performance of neurons. When wholesome, it carries a small variety of chemical tags referred to as phosphate teams. However when tau picks up too many of those chemical tags, it might clump collectively, resulting in irritation and nerve cell demise. The authors discovered that by blocking orexin receptors, lemborexant prevents extra tags from being added to tau, serving to tau keep its wholesome roles within the mind.
Holtzman mentioned his group is continuous to discover the explanations lemborexant remedy’s neuroprotective results had been seen solely in male mice. He speculated that the intercourse discrepancy might be as a result of commentary that feminine mice with the identical genetic predisposition to tau accumulation developed less-severe neurodegeneration in contrast with male mice. With much less injury to start with, potential useful results of the drug might have been smaller and harder to detect.
Reference: “Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse mannequin of tauopathy” by Samira Parhizkar, Xin Bao, Wei Chen, Nicholas Rensing, Yun Chen, Michal Kipnis, Sihui Music, Grace Gent, Eric Tycksen, Melissa Manis, Choonghee Lee, Javier Remolina Serrano, Megan E. Bosch, Emily Franke, Carla M. Yuede, Eric C. Landsness, Michael Wong and David M. Holtzman, 27 Could 2025, Nature Neuroscience.
DOI: 10.1038/s41593-025-01966-7
This work was supported by the Nationwide Institutes of Well being (NIH), grant numbers P01NS074969, RF1NS090934 and RF1AG061776; the JPB Basis; the Alzheimer’s Affiliation, grant quantity AARF-21-850865; the Rainwater Basis, and a COBRAS Feldman Fellowship.
Holtzman is an inventor on a patent licensed by Washington College to C2N Diagnostics on the therapeutic use of anti-tau antibodies. Holtzman cofounded and is on the scientific advisory board of C2N Diagnostics.
